As the utilization of active surveillance (AS) for prostate cancer (PCa) increases in the United States and worldwide, there also appears to be growing adoption of multiparametric magnetic resonance imaging (mpMRI) to guide management in the AS population.1–3 While much of the focus in the literature has been on using mpMRI in the initial diagnosis setting, proponents have recognized its value to risk stratify those who are eligible for or already enrolled in AS. A considerable proportion of the research related to PCa AS that was presented at the 2018 American Urological Association (AUA) annual meeting was devoted to understanding the role of mpMRI in the AS population to better risk stratify men who are at higher risk of disease progression.
Nationally, there has been consistent evidence showing an increase in AS utilization for the management of localized PCa while maintaining excellent longterm outcomes.1,4 Similar trends were reported at AUA 2018.5,6 The rise of AS has led others to identify variations in use of mpMRI in AS to better understand current clinical practices. Ginsburg and colleagues have reported via the Michigan Urological Surgery Improvement Collaborative (MUSIC) that 27.3% of patients received a mpMRI as a confirmatory test after enrollment in AS.7 mpMRI use was significantly greater in the privately insured population (30.2% vs 23.1%, P < 0.001) and declined with increasing patient age (39.1%, 30.7%, 27%, and 22% for men aged <50, 50-60, 60-70, and >70 years, respectively). Most importantly, however, they identified a significant regional variation in mpMRI use as well as other ancillary tests such as PCa genomic testing across the collaborative, which suggests a lack of consensus of its relative utility in clinical practice.7
Although the rise in AS uptake has been consistent nationally, the case for routine AS adoption for higher-risk patients has been less unanimous. African American (AA) men, previously thought to be disqualified from AS due to the higher rates of adverse pathologic features and worse outcomes after radical prostatectomy, are increasingly considered eligible for AS.8,9 Pinto and colleagues at the National Institutes of Health have added credibility to those advocating for inclusion of AA men in AS by showing no difference in mpMRI and pathologic findings between AA and non-AA men enrolled in AS.10 AA men had similar mpMRI lesion size, number of lesions, and surveillance biopsy pathology including number of positive cores and rates of grade reclassification (GR) compared to non-AA men. These findings are a positive step toward increasing the eligibility for men who may benefit from AS.
To better understand the financial burden on our healthcare system as AS expands, many studies presented at the AUA 2018 were focused on better understanding the cost effectiveness of AS relative to other treatments for localized PCa. Gaylis and colleagues showed that AS ($4072 ± $1354) was less than half as expensive per patient than other localized treatments for PCa such as radical prostatectomy (RP) ($9972 ± $1571), stereotactic body radiation therapy (SBRT) ($26,294 ± $2049), and intensity-modulated radiation therapy (IMRT/imageguided radiation therapy ($40,438 ± $2091).11 AS costs, however, were calculated assuming only a 21% rate of mpMRI use, which represents an underestimation of mpMRI utilization relative to other AS cohorts that may underestimate the relative financial value of AS compared with active treatment.7
In the current literature, the primary value of mpMRI in AS exists in an improved sensitivity for the detection of higher-grade PCa. Targeted biopsies in AS help identify those who were either initially misclassified prior to enrollment or those who progressed while in AS.12,13 However, more recently, including at AUA 2018, many researchers are focusing on using mpMRI to identify risk factors associated with GR in addition to singling out lower-risk men who may require less aggressive surveillance.14-16
Although prior studies have shown that targeted biopsy and systemic biopsy appear to be complementary in the AS population, Hsiang and colleagues reiterated the principle that mpMRI targeted and systematic biopsies should be performed together when possible to avoid missing GR.17,18 In their cohort, 27 (29%) men experienced GR. Of those, 8 (9%), 9 (10%), and 10 (11%) of men had GR on systematic biopsy only, targeted biopsy only, and both systematic and targeted biopsy, respectively. Pinto and colleagues, however, identified that when a targeted confirmatory biopsy is negative, men have more than a 50% reduction in their risk of GR (HR 0.40; 95% confidence interval (CI), 0.25-0.65; P < 0.001) and a median of 29 months longer time to progression.14 Therefore, targeted biopsies, which have become essential to the surveillance algorithm, also can be used to predict a lower likelihood of progression when negative.
AUA 2018 showed that mpMRI adds tremendous value to predicting those who are at risk for GR at surveillance biopsy, providing clinicians with more opportunities to develop a more sophisticated and individualized approach to AS. Mamawala and colleagues from the Johns Hopkins AS program showed that men with greater biopsy volume (>2 positive cores or >50% core involvement) at diagnosis and fewer prior biopsies (≤2 biopsies) had a higher risk of GR than men with low-volume disease (≤2 positive biopsy cores and ≤50% core involvement) and a greater number of surveillance biopsies (>5 biopsies).16 More interestingly, there was an elevated risk of GR for each of these variables across increasing Prostate Imaging Reporting and Data System (PI-RADS™) v2 scores, adding more understanding to the individualized risk of finding higher-grade disease. Carroll and colleagues from the University of California at San Francisco similarly identified a greater risk of GR as well as volume progression with higher PI-RADS v2 score in men with grade group (GG) 1 PCa.15 Relative to a PI-RADS v2 score of 1-2, a PI-RADS v2 5 lesion had a nearly three-fold risk of GR (HR 2.93; 95% CI, 1.61-5.32; P < .01). Surprisingly, for those who underwent RP, a PI-RADS v2 5 score was not associated with higher rates of adverse pathology.
Although many abstracts at AUA 2018 identified novel uses for mpMRI in AS, perhaps the most foreshadowing study of future uses for mpMRI in AS came from Huang and colleagues, who used quantitative mpMRI parameters to predict GR.19 They identified lower ADC values on baseline mpMRI in men with GR (median, 805 vs 930; P 5 0.01). Using an ADC cutoff of <700, there was a nearly 2-fold risk of upgrading to GG ≥2 and 2.5-fold risk of upgrading to GG ≥3 (HR = 1.9; 95% CI, 1.1-3.1; P = .01 and HR 5 2.5; 95% CI, 1.1-5.8; P = .04, respectively).
Recently, there has been a focus in the literature on the prognostic power of a negative mpMRI with a renewed focus in the AS population.20 Although a negative mpMRI by itself cannot be used to defer surveillance biopsy due to the 6% to 30% of GRs that would be missed, it may help risk-stratify men in AS to individualize care. Suardi and colleagues, from Milan, Italy, showed that a negative mpMRI, defined as a PI-RADS v2 score of ≤2, predicted a lower rate of early GR (OR 0.4; P = 0.01).20,21 Our cohort showed that for a truly negative mpMRI, without any visible lesion, only 4.6% of men experienced GR on surveillance biopsy, which stresses both its prognostic value while cautioning against avoiding surveillance biopsies altogether.22
An important underlying theme of much of the research at AUA 2018 was the use of mpMRI to identify men with more indolent PCa who may benefit from less-frequent surveillance biopsies. Although mpMRI alone cannot select these patients, the addition of biomarkers and other clinical variables appears to provide an additive benefit to ruling out GR.20,23 Eggener and Helfand showed that men in AS with a negative mpMRI, who have a prostate-specific antigen density (PSAD) <0.18 ng/mL2, and <4 positive cores on diagnostic biopsy had an area under the curve (AUC) of 0.86 and negative predictive value (NPV) of 96% for GR on surveillance biopsy.24 This cutoff would have spared 15.8% of men a biopsy while missing only a single patient. Our cohort at Johns Hopkins showed that the Prostate Health Index (PHI) appears to be superior to PSAD for ruling out GR when combined with mpMRI in AS.22 Using a PHI cutoff of 25.6 and PI-RADS v2 ≤3, a NPV of 98% could be achieved that would have spared 19.6% of surveillance biopsies at the cost of missing only 2.6% of GR.
AUA 2018 highlighted the growing body of evidence to support the remarkable prognostic value of mpMRI in the AS population. Much of the growing utility and adoption of AS for favorable-risk PCa depends on the improved risk stratification and cost-effectiveness provided by mpMRI.
Reviewed by Zeyad R. Schwen, MD and Alan W. Partin, MD, PhD, The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD